Curve Your Enthusiasm: Using AUC:MIC pharmacokinetics to optimize - PowerPoint PPT Presentation

Curve Your Enthusiasm: Using AUC:MIC pharmacokinetics to optimize vancomycin dosing AKPhA 2019 Ryan W. Stevens, PharmD, BCIDP Infectious Diseases Clinical Pharmacy Specialist Providence Alaska Medical Center Phone: 907-212-2252 Email: ryan.stevens@providence.org

Objectives: • Pharmacist: 1. Describe the pharmacokinetics/pharmacodynamics of vancomycin and factors which may impact efficacy or dosing of this drug. 2. Describe two methods of AUC:MIC vancomycin optimization and the pros/cons associated with each method. 3. Apply a linear/logarithmic trapezoidal AUC calculation model to vancomycin dosing in a patient case. • Technician: 1. Describe the mechanism of action of vancomycin. 2. Describe the basic pharmacokinetics/pharmacodynamics of vancomycin. 3. Describe 3 complexities in vancomycin dosing and why they represent a challenge.

Pre-assessment: • T/F: Vancomycin is a cell wall agent active at PBP2a • Vancomycin follows which pharmacodynamic models? ▫ T>MIC ▫ AUC:MIC ▫ Cmax:MIC • The AUC which represents the pharmacodynamic target for efficacy is _____? • The AUC which represents the threshold for toxicity is _____? • Which of the following are benefits of Bayesian AUC calculators over trapezoidal models? (choose all that apply) ▫ Less expensive ▫ Ability to adjust for changes to patient physiology ▫ Only requires one level ▫ Provides more accurate estimate of AUC

History: • Discovered by Eli Lilly Co. ▫ 1950 – Program launch to discover antibiotics for penicillin resistant S. aureus. ▫ 1952 – Antistaphylococcal activity seen in soil sample from Borneo.  Streptomyces orientalis ▫ 1958 – First approval by FDA • Initially dubbed “Mississippi Mud due to characteristic brown color. ▫ Difficult to process/remove https://en.wikipedia.org/wiki/Borneo impurities ▫ High degree of toxicities CID 2006;42 Suppl 1:S5-12.

History (continued): Papers published with “vancomycin” in the title: Slow to take off in the market… Vancomycin utilization (US, France, Italy, Germany, UK, Netherlands): Why? CID 2006;42 Suppl 1:S5-12.

MRSA’s Rise to Power: • 1959: Methicillin developed (remember… vanco 1958) • 1961: First methicillin resistant S. aureus (MRSA) identified • 1960-1967: Infrequent hospital outbreaks in Europe and Australia • 1968: First US hospital outbreak of MRSA in US (Boston, MA) • 1968-mid 1990s: MRSA gradually increases in incidence as hospital acquired pathogen (primarily urban hospitals) ▫ 1981: Large outbreak of MRSA in IVDU in Detroit ▫ 1986: Discovery of MecA gene and PBP2a hyper-expression ▫ Late 80s-Early 90s: Outbreak of MRSA among Australian Aboriginal populations without healthcare exposure • 1999-2008: Decade of community-acquired MRSA epidemic MRSA Research Center, The University of Chicago

Vancomycin: • Class: Glycopeptide • MOA: ▫ Inhibition of D-ALA-D-ALA cross linking of peptidoglycan ▫ Bactericidal (slowly) • Spectrum: Aerobic and anaerobic gram-positives • Adverse effects: ▫ “Red Man Syndrome” - >10%  Slow down the infusion ▫ Nephrotoxicity (to be addressed later) – 5-40% ▫ Neutropenia/leukopenia – 1-10% ▫ Ototoxicity – 1-9% (most associated with levels >40 mcg/mL) • Pharmacodynamics: AUC:MIC (>400 mg*h/L) Johns Hopkins Antibiotic Guide 2018

Nephrotoxicity: • Acute glomerular nephritis (AGN) • Rate: ▫ Initially thought to be “high” secondary to impurities in early product (i.e. Mississippi mud) ▫ IDSA Guidelines say < 5% incidence  Targeting old troughs: 5-10 mcg/mL ▫ Now studies with new troughs: 5-43% • Typical onset: 2-5 days into therapy • Typical peak: 5-10 days into therapy • Typical resolution time: >90% within 19 days ▫ ~3% will require hemodialysis Am J Health-Syst Pharm. 2009;66:82-98. Pharmacothearpy 2014;34(7):653-61.

Nephrotoxicity: • Know Risk Factors in Adults: ▫ Concurrent nephrotoxins  Amphotericin, aminoglycosides, IV contrast, loop diuretics, ACEi/ARBs (?), and piperacillin/tazobactam ▫ ACC admission ▫ Vasopressor administration ▫ Weight >/= 101 Kg ▫ History of acute or chronic kidney injury ▫ Empiric vancomycin doses >4 gm/day ▫ Prolonged courses (>5 days) ▫ Unstable renal function at baseline ▫ Initial trough (within 96 hours) level >20 mcg/mL ▫ Elevated AUC levels 600-800 within 48 hrs of initiation Am J Health-Syst Pharm. 2009;66:82-98. Pharmacothearpy 2014;34(7):653-61. Antimicrob Agent and Chemother 2008;52(4):1330-1336 Antimicrob Agents Chemother 2013;57(2): 734-744 AAC 2018;62(1):e01684-17

Toxicity: • Ototoxicity: ▫ Rate = 1-9% (older studies)  Currently relatively rare (esp. with monotherapy) ▫ Irreversible ▫ Additive when concurrent aminoglycoside use ▫ Correlations with levels:  Older studies = vanco concentrations >40 mcg/mL  New studies = no correlation with levels ▫ Usually high frequency hearing loss +/- tinnitus  Slow progression to total deafness Am J Health-Syst Pharm. 2009;66:82-98.

Other ADRs: 1,13 • Redman Syndrome: >10% (Infusion related) • Eosinophilia/neutropenia: 1-10% • Drug fever: 1-10% Am J Health-Syst Pharm. 2009;66:82-98. CID 2013;57(12):1760-5.

Vancomycin Pharmacokinetics: • Absorption: ▫ Little to no oral absorption • Distribution: ▫ Volume of distribution: 0.4-1 L/Kg (bad CSF unless inflamed meninges) ▫ Distribution phase (time): 0.5-1 hrs ▫ Protein binding (50-55%) • Metabolism: ▫ Little to no hepatic metabolism • Excretion: ▫ Excreted primarily as unchanged drug in the urine ▫ Half-life: 6-12 hrs (longer with renal impairment) Lexi-Comp Online 2018 CID 2006;42 Suppl 1:S35-9.

Pharmacodynamics: AUC = Area under the curve (i.e. area under the time/concentration curve) Note: AUC:MIC is expressed as a ratio!!!! Lowest possible concentration that inhibits visible bacterial growth after 18-24 hours of incubation https://www.ncbi.nlm.nih.gov/books/NBK266259/figure/introduction.f1/

S. aureus Vancomycin Susceptibility Breakpoints: • Per CLSI: ▫ ≤2 mcg/mL = Susceptible ▫ 4-8 mcg/mL = Intermediate WHAT?!?! ▫ ≥16 mcg/mL = Resistant These exist? • Current Evidence: ▫ Infections with MIC >1 mcg/mL:  Slower clearance of organism  Longer durations of vancomycin therapy  Higher vancomycin failure rate  Increased rate of mortality (bacteremia studies) CID 2012;54(6):755-771. CID 2008;46:193-200.

VSSA (25 nm) VISA and hVISA: • VISA = Vancomycin intermediate S. aureus ▫ First noted in Japan in 1997 ▫ Vancomycin MIC of 4-8 mcg/mL ▫ Mechanisms: hVISA (50 nm)  Increased cell wall thickness  Decreased D-ala-D-ala crosslinking  Decreased peptidoglycan turnover (remodeling)  Altered surface protein profile • hVISA = heterogeneously vancomycin intermediate S. aureus VISA (63 nm) ▫ Mixed population:  Some organisms with MIC of ≤2 mcg/mL  Some organisms with MIC of 4-8 mcg/mL ▫ Usually precedes full blown VISA J Yale Biol Med 2017;90:269-281. Ann Clin Microbio Antimicrob 2011;10:15.

“VRSA…the bacteria which must not be named...” Oritavancin Ceftaroline Delafloxacin Linezolid Tedizolid https://www.nme.com/news/film/fan-made-harry-potter-film-origins-vo-2219634 https://www.inverse.com/article/22110-harry-potter-spell-ranking • VRSA = Vancomycin Resistant S. aureus ▫ Resistance mediated by VanA or VanB genes  Native to Enterococcus faecium (VRE)  Resistance mediated by binding site alteration  D-ALA-D-ALA  D-ALA-D-LAC J Yale Biol Med 2017;90:269-281.

Current Guideline Recommendations: • Per IDSA Guideline ▫ “Based on evidence suggesting that S. aureus exposure to trough serum vancomycin concentrations of <10 mg/L can produce strains with VISA like characteristics, it is recommended that trough serum vancomycin concentrations always be maintained above 10 mg/L to avoid development of resistance. (Level of evidence = III, grade of recommendation = B.)” Am J Health-Syst Pharm. 2009;66:82-98.

Current Guideline Recommendations: • Per IDSA Guidelines: ▫ “ Based on the potential to improve penetration, increase the probability of optimal target serum vancomycin concentrations, and improve clinical outcomes for complicated infections such as bacteremia, endocarditis, osteomyelitis, meningitis, and hospital acquired pneumonia caused by S. aureus , total trough serum vancomycin concentrations of 15 – 20 mg/L are recommended. Trough serum vancomycin concentrations in that range should achieve an AUC/MIC of ≥ 400 in most patients if the MIC is ≤ 1 mg/L. (Level of evidence = III, grade of recommendation = B.)” Am J Health-Syst Pharm. 2009;66:82-98.

Current Guideline Recommendations: • Goal trough 15-20 mcg/mL: ▫ Endocarditis, MRSA bacteremia, osteomyelitis, meningitis, and MRSA pneumonia  ? Septic arthritis and necrotizing fasciitis • Goal trough 10-15 mcg/mL ▫ All other indications and organisms • But all-in- all… AUC:MIC ratio >400 mg*hr/L

MIC Variation by Testing Method: J Clin Microbiol 2013;51(7):2077-2081.